Fig. 5: TP53 deficiency enables increased proliferation under platinum treatment.
From: Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms
a Dose-response curves of MV4-11WT (circles) and MV4-11R248W, based on the DAPI-negative fraction of single cells (gating strategy in Supplementary Fig. 9b), n = 3 biological replicates per cell line (average of three clones). The complete dose-response model was tested against the null model, lacking genotype information (ANOVA). b The IC50 values of carboplatin treatment per genotype (average of three cells), extracted from the dose-response models depicted in (a). The comparison of the IC50 values is based on a z-test and error-bars represent the standard error (p = 1.58 * 10−27). c CellTrace™ signal per treatment condition, normalized to unit area, for MV4-11WT cells (top) and MV4-11R428W cells (bottom). Representative measurements for a single clone per genotype are shown. d Proliferation Score per treatment condition for MV4-11WT and MV4-11R248W. The scores of each cell line were compared within treatment conditions using a Holm’s corrected one-sided T-test (p = 0.0428, 0.00936, and 0.0366 for 0.37, 1.1, and 3.3 μM carboplatin, respectively). Error bars represent standard deviation of the mean of three independent experiments. e Normalized viability of CD34+ umbilical cord blood cells after 4, 8, and 12 days of carboplatin treatment (22.5 μM), based on the live cell count per condition. The viability was normalized to each matched untreated condition and compared using a Holm’s corrected one-sided T-test. Error bars represent the standard error of the mean of n = 3 biological donors, each examined in an independent experiment. f The KO score of the TP53 KO conditions based on ICE analysis (Synthego) with and without carboplatin treatment (22.5 μM). The KO score was compared using a one-sided paired T-test (p = 0.036, 0.012, and 0.036 for D4, D8, and D12, respectively) and each data point represents a biological replicate (n = 3 independent experiments, one unique biological donor per experiment). g The number of single base substitutions detected in WGS data of untreated and carboplatin-treated clonally expanded umbilical cord blood cells. h The 96-trinucleotide mutational profiles of the data shown in (g). i The cosine similarity between the mutational profile of carboplatin-treated umbilical cord blood cells and the mutational profile of in vivo platinum-based drug exposure (SBS31, SBS35, SBSD). NS not significant, ****p < 0.0001, **p < 0.01, *p < 0.05. Source data are provided as a Source Data file.
